Writing at ENV last month, I explained why proponents of intelligent design are justified in using the term “molecular machines.” Jonathan M., meanwhile, recently published a tremendous article here about the ATP synthase molecular machine, noting that scientists have called it a “bona fide rotary dynamo machine” with “ingeniously designed interfaces” making it “one of the most beautiful” enzymes in biology. Or, as another paper he cited pointed out, “Although there are other similar manmade systems like hydroelectric generators, F₀F₁-ATP synthase operates on the nanometer scale and works with extremely high efficiency.” Now I’ve just received a copy of a wonderful 2011 Cambridge University Press book, Molecular Machines in Biology: Workshop of the Cell, that contains additional insightful language about molecular machines.

In the Introduction, the book’s editor, Joachim Frank of the Department of Biochemistry and Molecular Biophysics at Columba University, gives a nice explanation of why we call them molecular machines:

Molecular Machines as a concept existed well before Bruce Alberts’ (1998) programmatic essay in the journal Cell, but his article certainly helped in popularizing the term, and in firing up the imagination of students and young scientists equipped with new tools that aim to probe and depict the dynamic nature of the events that constitute life at the most fundamental level. “Machine” is useful as a concept because molecular assemblies in this category share important properties with their macroscopic counterparts, such as processivity, localized interactions, and the fact that they perform work toward making a defined product. The concept stands in sharp contrast to the long-held view of the cell as a sack, or compendium of sacks, in which molecules engage and disengage one another more or less randomly. (p. 1)

The first chapter of the book, by Xinghua Shi and Taekjip Ha of the Department of Physics and Institute for Genomic Biology at the Howard Hughes Medical Institute of the University of Illinois at Urbana-Champaign, then add to the reasons why we call them molecular machines:

Molecular machines are molecule-based devices, typically on the nanometer scale, that are capable of generating physical motions, for example translocation, in response to certain inputs from the outside such as a chemical, electrical, or light stimulus. A large number of such sophisticated small devices are found in Nature, including the many biological motors discussed in this chapter, such as helicases and polymerases. These tiny nanomachines work in many ways just like an automobile on the highway, and many consume fuel on a molecular level, for instance through the hydrolysis of adenosine-5′-triphosphate (ATP) molecules, to power their motion on their tracks. As a result, when lacking the required fuel, these nanomachines tend to slow down and even stop, same as a motor vehicle would. In addition, these biological motors often move in a directional manner with variable speeds, and their processivity characteristics can be described by how far they move on their track of molecular highway. Motions of individual components with these protein machines, for example, the ribosome … , are often nicely coordinated like in any sophisticated, larger-scaled mechanical machines. (p. 4)

They go on to write:

In recent years, details of the composition, stoichiometry, and three-dimensional arrangement of components within many nanomachines have become available, thanks to the ever-increasing number of high-resolution crystal structures that have been solved, which have provided valuable insights into the mechanisms of how these biological motors accomplish their tasks. In the past two decades, researchers have also brought these machines under scrutiny by a number of novel and powerful methods with ultra-high sensitivity, watching their motions one molecule at a time, and have learned a great deal of previously hidden mechanistic details about their action and dynamics, such as the size of the fundamental steps taken by these motorized nanodevices. In a simplified view of the mechanism of action of biological motors, their strokes of physical translocation are powered by processes such as ATP hydrolysis through a modulation of their conformation, thus converting the chemical energy stored in the molecular fuel, in a stepwise fashion, into direction motions. (p. 4)

Could machines that produce directed motions arise through an undirected process like Darwinian selection? Whatever the cause of these molecular machines, it must be able to produce “highly fine-tuned” processes. Finn Werner and Dina Grohmann (both of the University College London Institute for Structural and Molecular Biosciences) explain what must be explained:

RNA polymerases (RNAPs) are essential to all life forms and responsible for the regulated and template DNA-dependent transcription of all genetic information. A plethora of basal and gene-specific transcription factors interact physically and functionally with RNAP, which results in the execution of a highly fine-tuned genetic program that is at the very heart of biology. (p. 78)

They further observe that “In the last decade, a large number of small non-coding RNA molecules have emerged as potent regulators of replication, transcription, translation, mRNA folding, and stability. Thus, RNA molecules are involved in all stages of the information processing in extant biology; they encode information and provide internal structure, regulatory and catalytic properties.” (p. 78) They then explore how the widespread use of RNA molecules emerged:

What is the reason for this pervasive omnipresence of RNA in life — is it due to the versatile properties of RNA alone, or is it a relic of the ancient past of our biosphere? Currently no theoretical models provide satisfying and unequivocal answers to the origins of life (Schuster, 2010). However, both the perpetuation of genetic information and the ability to alter the information by mutation or recombination was necessarily required for a hypothetical answer to be subject to Darwinian evolution.

They believe that the RNA world hypothesis might explain why RNA is ubiquitous throughout biology today. But they concede that the RNA world hypothesis faces key difficulties:

The “RNA world” hypothesis depends on a hypothetical ribozyme replicase that was responsible for the perpetuation of the genetic information and itself able to evolve – in effect, a ribozyme RNAP capable of synthesizing copies of itself and other RNA molecules. Even though no additional cofactors were required, the binding of small amino-acid-like molecules or even short protopeptides to the ribozyme could have increased its thermal and chemical stability, specificity, and interaction properties that, for example, favored binding of substrates or release of products. Notably no naturally occurring ribozyme RNA polymerases have been discovered yet. (p. 79)

However, they then counter that “in vitro evolution approaches starting from a pool of random sequences and driven by reiterated cycles of sequence alteration (mutation) and selection have generated both ribozyme RNA ligases and (relatively non-processive) RNAPs.” (p. 79, international citations removed) Of course those sorts of experiments may be called evolution by intelligent design. But are there other reasons why they don’t explain how RNAPs evolved? In fact, Werner and Grohmann are skeptical that such in vitro evolution experiments solve the problems associated with the RNA world:

One of the main objections raised against the putative ribozyme RNAPs is the apparent difficulty of synthesizing their nucleotide triphosphate substrates in the absence of proteinaceous enzymes. In an alternative scenario, the protein synthesis machinery (proto-ribosomes) evolved prior to nucleic acid polymerization; proto-enzymes were catalyzing the formation of nucleotides and their phosphates, and nucleic acid polymerases evolved without any ribozyme ancestors. This hyopothesis, however, fails to address the coding of the proto-enzymes, which would have been required for the necessary inheritability and principles of Darwinian evolution. (p. 79)

In other words, it’s very difficult to imagine how a ribozyme RNA polymerase could exist without the accompanying protein-based enzymes that aid in the process of RNA polymerization. As for those who hypothesize that the protein-synthesis machinery evolved first, their proposal also fails because it can’t explain how the machines became genetically encoded, since there would have been no way to replicate RNA prior to that time. The authors offer no solution, but instead note that “Currently no theoretical models provide satisfying and unequivocal answers to the origins of life,” citing a
2010 paper by Peter Schuster in the journal Complexity. Schuster wrote:

Debates on the origin of life-or more precisely the terrestrial origin of life-as well as the origin of the universe are followed with great interest in almost all human societies. In the latter case, there exists a standard model, the big bang theory derived from an extrapolation of elementary particle physics to the birth of our universe. Nothing comparable is at hand for origin of life studies. Many different ideas are competing and none is available to provide a sufficiently plausible root to the first living organisms.

(Peter Schuster, “Origins of Life: Concepts, Data, and Debates,” Complexity, Vol. 15(3) (2009).)

Taken together, all of this looks like an explicit admission that the origin of a crucial type of molecular machine — RNA polymerases — is a major problem, an unsolved one, for those who seek to understand the origin of life.